A disease caused by stress means that by psychosocial or physical stress stimulation (stressor), the distortion (response to stress) in the body subjected to these stimulations occurs and any disorders in systemic various areas develop. Concretely, since stressor influences (response to stress) on the activities of nervous system, endocrine system and immune system to void these functions, these influences lead to organic lesions in brain itself or peripheral organs. In case of being subjected to excess stress, it causes diseases leading to marked reduce of quality of life (so-called, QOL).
Diseases caused by stress include, for example, central nervous system diseases (e.g. depression etc.), digestive system diseases (e.g. irritable bowel syndrome, gastric ulcer etc.), cardiovascular system diseases (e.g. essential hypertension etc.) and the like. As medicinal drugs for remedy for diseases caused by these stresses, anti depressant drug, anti anxiety drug and drug for symptomatic treatment against organic lesions of peripheral organs (e.g. antacids, gastric mucoprotective drugs etc.) have been developed for the purpose of alleviating psychological stressor. However, these drugs become effective to some extent, but these addictions, side effects or the like frequently develop. At present, the therapy for these diseases comes to definitive therapy. Therefore, the development of the preventing and/or therapeutic drug for diseases caused by stress having highly safety and coming to possible definitive therapeutic drug has been longed for.
Meanwhile, there are mitochondrial benzodiazepine receptor (hereinafter, it is abbreviated as MBR.) (“Science 198, 849-851, 1977”, “Proc. Natl. Acad. Sci., 89, 3805-3809, 1977”) in mitochondrial outer membrane, which transport cholesterol from intracellular to the internal membrane of mitochondria that is the active site of P-450 sec. Steroid synthesized in the brain is called as neurosteroid. Cholesterol, which is the steroid precursor, is converted into pregnenolone metabolized with side-chain cleavage enzyme P-450 scc. This process is the first process of steroid production system. However, it has been indicated that this transport process was the rate determining process in steroid production system rather than metabolism with P-450 scc. It has been thought that the neurosteroid content in the brain could be adjusted if the function of MBRs could be regulated. It has been thought that as a result of balance between an excitatory signaling system and an inhibitory signaling system was collapsed by neurosteroid content in the brain varying under stress condition, the various stress-related diseases could be caused by changes of activities in nerve system, immune system and endocrine system which were regulated by these nerve systems.
As mentioned above, the disrupted balance between an excitatory signaling system and an inhibitory signaling system caused by stress or load can be improved to the desirable balanced condition by the increase or the inhibition of neurosteroid production, which is useful for prevention or treatment for stress-related diseases. Therefore, it is expected that the compounds having affinity for MBRs are extremely useful for prevetion and/or treatment for these diseases, if they are supplied
As the preventive and/or therapeutic agent for a disease caused by stress, the compound represented by formula (Y):AY-XY—YY—ZY—BY  (Y)(wherein, AY is cyclic group which may have a substituent(s), XY, YY and ZY are each independently single bond or a spacer of which main chain has an atom number of 1-3, BY is hydrocarbon which may have a substituent(s) or cyclic group which may have a substituent(s)), a salt thereof, a N-oxide thereof, a solvate thereof or a prodrug thereof is known to have the affinity to MBRs (see, WO04/113300).
In addition, as tri-cyclic compound (β-carboline derivative), the compounds represented by formula (Z):
(wherein, R0Z is halogen atom, C1-6 alkyl etc.; R1Z is aryl which may be substituted etc.; R2Z is hydrogen atom, C1-6 alkyl etc.; R3Z is hydrogen atom, C1-6 alkyl, aryl etc.; XZ is C(═O), SO2, C(═O)NRaZ etc.; Y is (CH2)nZ aryl etc.; nZ is 0-4), a pharmaceutically acceptable salt thereof or a solvate thereof has been known as phosphodiesterase inhibitor (see, WO02/064591).